To clarify the joint effects of environmental and genetic factors in the etiology of breast cancer, the NIEHS is carrying out a prospective study of a cohort of unaffected sisters of women who have had breast cancer. Participants will be recruited over 3-4 years, beginning Fall 2002. The NIEHS Sister Study will prospectively examine environmental and familial risk factors for breast cancer and other diseases in a cohort of 50,000 sisters of women who have had breast cancer. Such sisters have about twice the risk of developing breast cancer as other women. The frequency of any relevant genes and shared risk factors will also be higher, thus enhancing the statistical power of the study to detect risks. Sisters are expected to be highly motivated and response rates and compliance over time are expected to be high. Thus, studying sisters will enhance our ability to understand the interplay of genes and environment in breast cancer risk and to identify potentially preventable risk factors. The prospective design will allow us assess exposures before the onset of disease thus avoiding biases common to retrospective studies and aiding in causal interpretation. The study will create a framework from which to test new hypotheses as they emerge. Cancer-free sisters will be recruited nationally through health professionals, breast cancer advocates, the Internet, and a national advertising campaign. Recruitment strategies will maximize inclusion of minorities and high-risk women. Women with newly diagnosed breast cancer (up to 1,500) may be included if their cancer-free sister also enrolls. These incident cases will be compared to their cancer-free sisters in a retrospective study and will be followed prospectively to assess the influence of genes and environment on prognosis. Data on potential risk factors and current health status will be collected using computer assisted telephone interviews and mail questionnaires. Blood, urine, and environmental samples will be collected and banked for future use in nested studies of women who develop breast cancer (or other diseases) and a sample of those who don't. The cohort will be followed prospectively for 10 or more years. Annual questionnaires will update medical history and changes in exposures. Medical records and tumor tissue will be retrieved for those who develop cancer. Medical records will also be sought to facilitate the study of other diseases of importance to women. 1500 new cases of breast cancer are expected to occur in the cohort after five years. Analyses will assess the independent and combined effects of environmental exposures and genetic polymorphisms that affect estrogen metabolism, DNA repair, and response to specific environmental exposures. Future analyses will focus on known and potential risk factors (e.g. smoking, occupational exposures, alcohol, diet, obesity) in include measurement of phthalates, phytoestrogens, and metals in blood and urine, insulin, growth factors, vitamins and nutrients, and genes. Ancillary studies will compare unaffected and affected sisters with breast cancer, compare characteristics of tumors in pairs of sisters with breast cancer, and explore risk for other diseases (e.g. heart disease, osteoporosis, other hormonal cancers, and autoimmune diseases) as well as explore genetic and environmental effects on prognosis.